Drug-release properties of sustained-release of anti-tuberculosis drugs composite HRZ/PLGA bone graft material in spinal tuberculosis in rabbits

English Keywords:Spinal tuberculosis  Triple anti-tuberculosis drugs  Coating material  In vivo  Slow release

English Abstract:

  【Abstract】 Objectives: To observe the drug-release properties of sustained-release of anti-tuberculosis drugs and bone graft complex in spinal tuberculosis in rabbits. Methods: Spinal tuberculosis model was introduced in 120 rabbits. The models were randomly divided into sustained-release material group(group A), local administration group(group B), oral gavage group(group C) and sham operation group(group D) based on the dosage and administration of isoniazid(INH, H), rifampicin(RFP, R) and pyrazinamide(PZA, Z). Among them, the rabbits of group A, B and C underwent L4/5 spinal tuberculosis debridement and autologous iliac bone graft surgery, group D underwent sham surgery. The concentration of H, R and Z in the focal bone tissue was detected by the method of high performance liquid chromatography(HPLC) on the 3rd, 7th, 14th, 28th, 56th and 84th day after surgery. Then the drug concentration-time curve was drawn, followed by analyzing the pharmacokinetic parameters by DAS software 3.2.1. Results: The highest concentration of H, R and Z in the focal bone tissue was detected on the 3rd day in group A, thereafter the concentration decreased gradually over time. By the 84th day, the concentration reached the lowest point(H, 6.69±1.42μg/ml; R, 6.28±0.77μg/ml; Z, 19.88±0.90μg/ml). The concentration of all the three drugs was 10 times higher than MIC in each detecting time point, which was known as minimal inhibitory concentration. Comparing the concentration of each drug at different detecting time points, a significant level was set at P<0.05. In group B, the detecting concentration of H, R and Z in the focal bone tissue significantly increased on the 3rd day, then dropped sharply over time, which became undetectable on the 14th day. While the difference between concentration of each drug on the 3rd day and that on the 7th day was statistically significant(P<0.05). The concentration of H, R and Z in the focal bone tissue was kept in a relatively stable low level over time in group C and group D. In group C, on the 84th day after surgery, the concentration of H was 3.21±0.32μg/ml, R was 3.68±0.42μg/ml, and Z was 6.68±0.25μg/ml. In group D, on the 84th day after surgery, the concentration of H was 3.24±0.33μg/ml, R was 3.53±0.44μg/ml, and Z was 6.39±0.45μg/ml. Pairwise comparisons of concentration of each drug detected at different time points did not show statistically significant difference(P>0.05). Comparing the concentration of each drug at the same time point among group A, B, C and D, there was no significant difference in the same time between group C and D(P>0.05). The drug concentration-time curves in group A, C and D were flat, without burst release, and the concentration of H, R and Z in group A was higher than that in group C and group D. On the 84th day, the concentration of H, R and Z in group A was 3.02, 1.7 and 2.97 times as high as that in group C, respectively, and a significant level was set at P<0.05. In group B, there was a significant burst release phenomenon. The drug concentration dropped sharply, and on the 14th day, there was no H, R or Z detected. Pharmacokinetic data analysis: the area under the curve, the biological half-life in group A were significantly higher than those in group B and group C, and the difference was statistically significant(P<0.05). Conclusions: The three drugs in slow-releasing anti-tuberculosis drugs bone graft complex is sustained, efficient and gentle release locally in the model of spinal tuberculosis in rabbits.